The present invention relates to a process for preparing 2-hydroxycarboxylic esters having a quaternary xcex2-carbon atom.
Endothelin receptor antagonists are novel active compounds for the treatment of various cardiovascular disorders. WO 97/38981 describes various endothelin receptor antagonists, for example (S)-3,3-diphenyl-2-(4,6-dimethylpyrimid-2-yloxy)butyric acid. According to the description in WO 97/38981, this compound is obtained from (S)-2-hydroxy-3,3-diphenylbutyric acid by reaction with 4,6-dimethylpyrimidin-3-yl sulfone. 2-Hydroxy-3,3-diphenyl-butyric acid for its part is obtained by reducing 2,2-diphenylpropionitrile to the aidehyde, which is converted into the cyanohydrin which is then subjected to acid hydrolysis. However, this process has a number of disadvantages. The cyanohydrin synthesis involves the handling of hydrogen cyanide, which is objectionable for safety and health reasons. Furthermore, 2,2-diphenylpropionitrile is a comparatively expensive starting material, and the overall yield obtained by this route is unsatisfactory.
It is an object of the present invention to provide an alternative process for preparing 2-hydroxycarboxylic acids having a quaternary xcex2-carbon atom, and/or esters thereof.
Fukumasa et al., THL 32 (1991), 1059-1062, describe the reaction of monosubstituted epoxides with trimethylaluminum.
Danishewsky, S. et al., J. Org. Chem. 41 (1976), 1669-1671, describe the use of functionalized alanes for converting epoxides into trans-fused xcex3-lactones.
Kuran, W. et al., J. Organomet. Chem 73 (1974), 187-193, describe the reaction of methylaluminum compounds with propylene oxide.
Visnick, M. et al. Synthesis 1983, 284-287, describe the addition of t-butoxycarbonylmethyldiethylalane to 1-alkylidene-2,3-epoxy-3-methylcyclohexanes.
Pfaltz, A. et al., Angew. Chem. Int. Ed. Engl. 21 (1982), 71, report the regioselective ring-opening of xcex1- and xcex2-alkoxyepoxides with trimethylaluminum in the presence of catalytic amounts of butyllithium or lithium methoxide.
Alexakis, A. et al., Tetrahedron 45 (1989), 6197-6202, describe the boron-trifluoride-supported ring-opening of epoxides by lithium alkenyl aluminate reagents. The epoxides used were cyclohexene oxide and n-butyl epoxide.
In a general manner, Gorzynski-Smith, J., Synthesis 1984, 634, refers to the possibility of reacting epoxides with organoaluminum compounds. Simple trialkyl alanes are said to be of limited utility, since the reaction is accompanied by undesirable side-reactions, such as the reduction of the epoxide.
Miyashita, M. et al., J. Org. Chem. 56 (1991), 6483-6485, describe the stereospecific methylation of xcex3,xcex4-epoxy acrylates by trimethylaluminum in the presence of water. Miyashita, M. et al., Tetrahedron Asym. 4 (1993), 157.3-1578, describe the use of the epoxide ring-opening with trimethylaluminum in the presence of water in the synthesis of (xe2x88x92)-serricornin. Miyashita, M. et al., Chem. Soc., Chem. Commun. 9 (1996), 1027-1028, describe the use of the epoxide ring-opening with trimethylaluminum in the presence of water in the synthesis of the ansa chain segment of streptovaricin U.
Poon, T. et al., Synthesis 1998, 832, disclose the following reaction: 
The above literature references do not disclose any reactions in which the epoxide ring carries an ester group.
Neukom, C. et al., J. Am. Chem. Soc. 108 (1986), 5559-5568, describe the reaction of ethyl trans-2,3-epoxybutyrate with diethylpropynylalane. Bartlett, A. et al., J. Org. Chem. 47 (1982), 3941-3945, describe the reaction of ethyl trans-2,3-epoxybutanoate with diethyltrimethylsilylethylalane. The conversion into the xcex1-hydroxy esters with a tertiary xcex2-carbon atom succeeds with only moderate yields.
We have found that the object of the invention is achieved by a process for preparing 2-hydroxycarboxylic esters of the formula I 
in which
R1 and R2 independently of one another are C1-C20-alkyl, C3-C8-cycloalkyl, C2-C20-alkenyl, C2-C20-alkynyl,C6-C10-aryl, C7-C14-aralkyl or C7-C20-alkylaryl, or R1 and R2 together with the carbon atom to which they are attached form a 5- to 8-membered ring;
R3 is C1-C20-alkyl, C2-C20-alkenyl or C2-C20-alkynyl;
R4 is C1-C20-alkyl, C3-C8-cycloalkyl, C2-C20-alkenyl, C2-C20-alkynyl, C6-C10-aryl, C7-C14-aralkyl or C7-C20-alkylaryl;
which comprises reacting a glycidyl ester of the formula II 
in which R1, R2 and R4 are as defined above with an organoaluminum reagent of the formula III 
in which R3 is as defined above, X in each case independently have the meanings given for R3 or are halogen or C1-C4-alkoxy and n is from 0 to 10.
Suitable C1-C20-alkyl groups are straight-chain and branched alkyl groups, for example C1-C8-alkyl, such as methyl, ethyl, propyl, n-butyl, isobutyl, t-butyl, pentyl.
Suitable C3-C8-cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Suitable C2-C20-alkenyl groups are, preferably, C1-C8-alkenyl, such as vinyl, allyl, 1-hexenyl.
Suitable C2-C20-alkynyl groups are, preferably, C1-C8-alkynyl, for example ethynyl or propynyl.
Suitable C6-C10-aryl groups are, in particular, phenyl or naphthyl.
Suitable C7-C14-aralkyl groups are, for example, benzyl or phenethyl.
Suitable C7-C20-alkylaryl groups are, for example, 2-, 3-, 4-methylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-dimethylphenyl or 2,4,6-trimethylphenyl.
Preferably, at least one of the radicals R1 and R2 is aryl, aralkyl or alkylaryl, cycloalkyl or branched alkyl, in particular alkyl having a branch in the 1- or 2-position, such as isopropyl, t-butyl, isobutyl.
Particularly preferably, R1 and R2 are both phenyl.
R1, R2 and R3 may carry 1, 2, 3, 4 or 5 substituents which do not negatively affect the reaction according to the invention, such as, for example, C1-C6-alkyl, C1-C6-alkoxy, di(C1-C6-alkyl)amino, nitro, ester (for example CO2R5, where R5 may have the meanings given for R4), amide, sulfonamide, silyl or nitrile groups.
The glycidyl esters of the formula II can be obtained, for example, by Darzens glycidyl ester synthesis from corresponding ketones, by reaction with chloroacetic esters and base. Furthermore, they can be obtained, for example, by epoxidation of suitably substituted cinnamic esters. They may have the (S) or (R) configuration at the xcex1-carbon and may be present as pure or enriched enantiomers or as racemate. If R1xe2x89xa0R2, it is also possible for both configurations to be present at the xcex2-carbon.
R3 is preferably methyl, ethyl, n-butyl, particularly preferably methyl. R3 may furthermore be, for example, AlkOCOxe2x80x94CH2xe2x80x94, AlkOxe2x80x94Cxe2x89xa1Cxe2x80x94, Alk-Cxe2x89xa1Cxe2x80x94, Alk-CHxe2x95x90CHxe2x80x94, Alk-CHxe2x95x90CHxe2x80x94CH2xe2x80x94, in which Alk is C1-C4-alkyl.
In the formula III, X has the meanings given for R3, in particular C1-C4-alkyl; halogen, such as fluorine, chlorine or bromine; or C1-C4-alkoxy.
The index n is preferably 0. Particularly preferred organoaluminum reagents are trimethylaluminum, triethylaluminum and tributylaluminum, trimethylaluminum being most preferred. Other suitable reagents are, for example, AlkOCOCH2Al(C2H5)2, Alk-CHxe2x95x90CHxe2x80x94Al(C2H5)2.
Organoaluminum reagents in which nxe2x89xa00 are known under the term alumoxanes, and they can be obtained by controlled reaction of aluminum organyls with water (cf., for example, DE-A-37 31 665).
The reaction according to the invention of the glycidyl ester of the formula II with the organoaluminum reagent of the formula III is preferably carried out at a temperature of less than 20xc2x0 C., in particular at from xe2x88x9210 to +10xc2x0 C.
The reaction according to the invention is advantageously carried out in a nonpolar solvent, preferably an aliphatic or aromatic hydrocarbon or a mixture of aliphatic and/or aromatic hydrocarbons, such as hexane, heptane, cyclohexane, benzene, toluene or xylene.
The reaction time is generally from 0.5 to 2 h. After the reaction has ended, the reaction mixture is generally worked up acidic-aqueous; the 2-hydroxycarboxylic ester of the formula I is isolated by customary methods. If desired, the ester can be converted into the parent acid.
In the reaction according to the invention, the organoaluminum reagent of the formula III is preferably employed in excess. Particularly preferably, the molar ratio of the organoaluminum reagent of the formula III to the glycidyl ester of the formula II is in the range from 1.3 to 1.5. Higher excesses of organoaluminum reagent of the formula III may lead to a worsening of the regioselectivity.
The reaction according to the invention can be carried out both by adding the organoaluminum reagent to a solution of the glycidyl ester, preferably in a nonpolar solvent, or by adding the glycidyl ester, preferably as a solution in a nonpolar solvent, to a solution of the organoaluminum reagent. A reaction procedure where a solution of the glycidyl ester in toluene is added to a solution of the organoaluminum reagent in heptane or cyclohexane has been found to be particularly useful.
In the reaction according to the invention, the radical R3 is introduced substantially regioselectively into the xcex2-position to the ester group. The regioselectivity is generally more than 80%, preferably more than 90%. The reaction takes place predominantly with retention of the configuration at the carbon which carries the ester group. If glycidyl esters having a defined stereochemistry are used, it is therefore possible to obtain essentially pure enantiomers.
Surprisingly, the reaction of the glycidyl ester with the organoaluminum reagent generally succeeds without addition of further activating reagents, such as tertiary amines, lithium alkoxides or lithium alkyls, even if the starting material used is a sterically hindered glycidyl esters.
Surprisingly, in the reaction of the glycidyl ester with the alkylaluminum reagent, there are furthermore no side-reactions, such as, for example, elimination to give xcex1,xcex2-unsaturated esters, or pinacol rearrangements, to be observed. This is particularly surprising, since trialkylaluminum, for example, is known to catalyze pinacol rearrangements.